Osteoarthritis (OA) is a progressive joint disease, which is characterized by the breakdown of joint cartilage. It may affect one or more joints in the body, including those of the fingers, neck, shoulder, hips, knees, lower spine region, and feet. OA can cause pain and severely impair mobility and lower extremity function (E. Bagge et al., Age Ageing, 1992, 21: 160-167; D. Hamerman, Ann. Rheum. Dis., 1995, 54: 82-85; J. Jordan et al., J. Rheumatol., 1997, 24: 1344-1349; S. M. Ling and J. M. Bathon, J. Am. Geriatr. Soc., 1998, 46: 216-225), which can lead to disability and difficulty maintaining independence (A. A. Guccione et al., Am. J. Public Health, 1994, 84: 351-358; M. A Gignac et al., J. Gerontol. B: Psychol. Sci. Soc. Sci., 2000, 55: 362-372; M. C. Corti and C. Rignon, Aging Clin. Exp. Res., 2003, 15: 359-363). OA is associated with aging: the prevalence of radiographic osteoarthritis is less than 1% in people under 30 years of age but, with increasing age, the prevalence rises sharply and was found to be approximately 80% in individuals over 65 (R. C. Lawrence et al., J. Rheumatol., 1989, 16: 427-441; E. Bagge and P. Brooks, Drugs Aging, 1995, 7: 176-183; N. J. Manek and N. E. Lane, Am. Fam. Physician., 2000, 61: 1795-1804). Despite being a condition that causes most problems to populations after retirement age, OA is also rated the highest cause of work loss in the U.S. and Europe. In addition to age, risk factors known to be associated with OA include obesity, traumatic injury and overuse due to sports or occupational stresses. However, the precise etiology of osteoarthritis is still unknown.
Currently, diagnosis of OA is typically based upon radiological examination as well as clinical observations including localized tenderness, use-related pain, bony or soft tissue swelling, joint instability, limited joint function, muscle spasm, and crepitus (i.e., cracking or grinding sensation). While the diagnosis of OA is often suggested on physical examination, radiographic evaluation is generally used to confirm the diagnosis or assess the severity of the disease. The radiographic hallmarks of OA include non-uniform joint space loss, osteophyte formation, cyst formation, and subchondral sclerosis. While these characteristic features are generally present in X-ray images of “severe” or “late” OA, patients with “early” OA may not show radiographic evidence of bony changes, joint space narrowing and/or osteophytosis, making the diagnosis unclear or difficult to establish. In the absence of a reliable diagnosis, physicians cannot intervene early in the course of the disease, i.e. before signs of joint destruction arise. Magnetic resonance imaging (MRI) is used for delineating articular cartilage morphology and composition, particularly in large joints such as the knee, and can reveal cartilage defects and thinning regions of the joint not visible with radiography (K. Ott and J. Montes-Lucero, Radiol. Technol., 2002, 74: 25-42; F. Eckstein and C. Glaser, Semin. Mucculoskelet. Radiol., 2004, 8: 329-353; G. A. Tung, Med. Health R. I., 2004, 87: 172-175). However, recent studies indicate that MRI may not be very useful in diagnosing OA, due to the frequent incidence of meniscal tears, which may appear both in the presence or absence of knee pain and/or other symptoms of osteoarthritic disease (M. Englund, et al., The New England Journal of Medicine, 2008, 359; 11: 1108-1115).
An additional diagnostic method for OA is arthroscopy, in which a small incision in the patient's skin is made and fiber optic instruments are inserted into the joint. This procedure allows the visualization of the interior of the joint through this very small incision rather than a large incision needed for surgery. However, this technique is invasive, expensive, and may lead to additional pain in the joint. Therefore, alternative, less costly and invasive diagnostic procedures are desirable.
There is currently no cure for OA, and available osteoarthritis therapies are directed at the symptomatic relief of pain, and at improving and maintaining joint function. Furthermore, in the context of the recent withdrawals of COX-2 inhibitors, physicians are even more limited in their choice of treatments for OA. The demand for disease-modifying drugs for OA has grown considerably as awareness of the profound social and economic impact of this prevalent and debilitating disorder has become widespread. However, clinical trials of such drugs rely on the assessment of changes in joint space observed using plain X-rays (S. A. Mazzuca et al., Osteoarthritis and Cartilage, 1997, 5: 217-226). Since changes caused by articular cartilage loss are small (1-2 mm per year), a minimum of one year is required before sufficient changes have occurred to be detectable and, therefore, before a drug's efficacy can be assessed.
Clearly, there is a great need for biological markers of OA and OA progression. In particular, biomarkers that would allow reliable diagnosis and monitoring in the early stages of the disease and permit early intervention to potentially prevent pain and long-term disability are highly desirable. Also needed are biomarkers and design assay systems that could evaluate the efficacy of disease-modifying OA drugs in a time frame significantly shorter than the year currently required for assessment of radiological changes.